The etiology of Parkinson's disease (PD) involves both genetic and enviromental factors. The risk of Parkinson's disease is higher among relatives of cases than controls but only a few multigenerational families have been identified. A mutation in the gene for alpha synuclein of chromosome 4 has recently been identified in 4 such families. In support of environmental causes, are the observations that MPTP and occupational managanese exposure induce PD. Iron accumulates in the substantia nigra in PD while ferritin concentrations are reduced. This imbalance of iron may accelerate free radical formation and lipid peroxidation. In PD, activity in complex 1 of the respiratory chain is reduced in the nigra. MPTP inhibits NADH-CoQ reductase (complex 1) in mitochondria while manganese inhibits the citric acid cycle enzyme mitochondrial aconitase (ACO2). Deficits in ATP production may indirectly contribute to the pathogenesis of PD. We have found that in comparison to controls, patients with PD have lower concentrations of iron storage and transport proteins indicating a pertubation in systemic iron metabolism. We have alse detected a shifted protein band in serum which contains ACO2. We also found evidence for allelic association of two dinucleotide repeat markers on chromosome 22q13 which includes the ACO2 gene. These observations lead us to hypothesize that PD may be the result of a mutation, splicing variant or posttranslational modification of ACO2 which, in turn alters mitochondrial function. We will investigate changes in iron metabolism and caloric intake in Parkinson's Disease over time and at two critical stages: early (untreated) and late. We will also characterize and determine the frequency of altered forms of ACO2 in PD and controls and investigate mitochondrial function in relation to altered ACO2.